PKM2 Isoform-Specific Deletion Reveals a Differential Requirement for Pyruvate Kinase in Tumor Cells

被引：463

作者：

Israelsen, William J. ^{[1
]}

Dayton, Talya L. ^{[1
]}

Davidson, Shawn M. ^{[1
]}

Fiske, Brian P. ^{[1
]}

Hosios, Aaron M. ^{[1
]}

Bellinger, Gary ^{[1
]}

Li, Jie ^{[2
]}

Yu, Yimin ^{[1
]}

Sasaki, Mika ^{[3
]}

Horner, James W. ^{[4
]}

Burga, Laura N. ^{[3
]}

Xie, Jianxin ^{[5
]}

Jurczak, Michael J. ^{[6
]}

DePinho, Ronald A. ^{[4
]}

Clish, Clary B. ^{[7
]}

Jacks, Tyler ^{[1
]}

Kibbey, Richard G. ^{[6
,8
]}

Wulf, Gerburg M. ^{[3
]}

Di Vizio, Dolores ^{[9
,10
,11
]}

Mills, Gordon B. ^{[2
]}

Cantley, Lewis C. ^{[3
,12
]}

Vander Heiden, Matthew G. ^{[1
,4
]}

机构：

[1] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[3] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Dept Med, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[5] Cell Signaling Technol, Danvers, MA 01923 USA

[6] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA

[7] Broad Inst, Cambridge, MA 02142 USA

[8] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA

[9] Cedars Sinai Med Ctr, Div Canc Biol & Therapeut, Los Angeles, CA 90048 USA

[10] Boston Childrens Hosp, Urol Dis Res Ctr, Boston, MA 02115 USA

[11] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA

[12] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

来源：

CELL | 2013年 / 155卷 / 02期

关键词：

GENE-TRANSCRIPTION; HNRNP PROTEINS; M2; ISOFORM; CANCER; GROWTH; METABOLISM; PROMOTES; ACTIVATION; MICE; PHOSPHORYLATION;

D O I：

10.1016/j.cell.2013.09.025

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The pyruvate kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable pyruvate kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active pyruvate kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells.

引用

页码：397 / 409

页数：13

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